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Published Online November 20, 2002
Science DOI: 10.1126/science.1078456

Reports

Submitted on September 16, 2002
Accepted on October 26, 2002

NPAS2: A Gas-Responsive Transcription Factor

Elhadji M. Dioum 1, Jared Rutter 2, Jason R. Tuckerman 1, Gonzalo Gonzalez 1, Marie-Alda Gilles-Gonzalez 1*, Steven L. McKnight 2*

1 Departments of Biochemistry and Plant Biology and Plant Biotechnology Center, Ohio State University, 1060 Carmack Road, Columbus, OH 43210, USA.
2 Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

* To whom correspondence should be addressed. E-mail: magg{at}biochem.swmed.edu, steven.mcknight{at}utsouthwestern.edu.

Neuronal PAS domain protein 2 (NPAS2) is a mammalian transcription factor that binds DNA as an obligate dimeric partner of BMAL1 and has been implicated in the regulation of circadian rhythm. Here we show that both PAS domains of NPAS2 bind heme as a prosthetic group, and that the heme status controls DNA binding in vitro. NPAS2:BMAL1 heterodimers, existing in either the apo (heme-free) or holo (heme-loaded) state, bound DNA avidly under favorably reducing ratios of NADP(H). Low micromolar concentrations of carbon monoxide inhibited the DNA binding activity of holo-NPAS2 but not that of apo-NPAS2. Upon exposure to carbon monoxide, active BMAL1 homodimers were formed at the expense of NPAS2:BMAL1 heterodimers. These results indicate that the heterodimerization of NPAS2, and presumably the expression of its target genes, are regulated by a gas through the heme-based sensor described here.


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